We have recently demonstrated that the shared epitope (SE) contributes to rheumatoid arthritis (RA) pathogenesis by acting as a ligand that activates pro-osteoclastogenic signal transduction events. Given the association between RA and periodontal disease (PD), and the association of both conditions with HLA-DRB1 alleles that code the SE motif, here we will examine the hypothesis that this motif may directly contribute to bone damage severity in PD due to its signal transduction effects. The research plan has 2 specific aims: Specific Aim 1 will examine the effect of an exogenously added SE in a mouse model of PD, using a novel small SE-mimetic compound, cQKRAA which contains a common SE sequence motif. This SE-mimetic ligand has been recently shown to have potent pro-osteoclastogenic effects in vitro and in vivo. In Specific Aim 2 we will examine the effect of endogenous SE, using transgenic mice expressing HLA-DR molecules with the SE sequence, or control SE-negative sequence. In preliminary studies, the SE transgenic mice were found to have enhanced osteoclastogenic propensity. In both aims, the specificity of the SE effects on the severity of PD will be determined by inhibiting it with a novel specific SE-antagonistic compound. Thus, using novel research tools, the proposed studies will examine a new concept in the pathogenesis of PD. In the long run, the proposed research could provide a scientific basis for future studies to develop new therapeutic strategies for this common disease.